Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and methods of female contraception. Estetrol is a biogenic estrogen that is endogenously produced by the fetal liver during human pregnancy. Recently, estetrol has been found effective as an estrogenic substance for use in HRT. Other important applications of estetrol are in the fields of contraception, therapy of auto-immune diseases, prevention and therapy of breast and colon tumors, enhancement of libido, skin care, and wound healing.
The synthesis of estetrol and derivatives thereof is known in the art. J. FISHMAN and H. GUZIK (J. Org. Chem, Vol 33, No 8, 3133-3135, 1968) describe a route to estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol (estetrol) involving cis hydroxylation of the double bond of an α-β-unsaturated dioxolane derivative of formula A, wherein Ac is acetyl.

Osmium tetraoxyde was used for the cis hydroxylation of compound (A) and gave the 17,17-ethylenedioxyestra-1,3,5(10)-triene-3,15α,16α-triol 3-acetate as the major product. However attempts to remove the dioxolane group failed completely.
The carbonyl group at C17 of the 3-hydroxyestetra-1,3,5(10),15-tetraen-17-one was reduced with LiAlH4 to estra-1,3,5(10),15-tetraene-3,17-diol that was isolated as the diacetate (compound B). Compound B was subjected to cis-hydroxylation of the double bond of D ring by using Osmium tetraoxyde which resulted into the formation of estra-1,3,5(10)-triene-3,15α,16α,17α-tetraol-3,17-diacetate (compound C) as the major product associated with estra-1,3,5(10)-triene-3,15β,16β,17β-tetrol-3,17 diacetate. These compounds were isolated by thin layer chromatography. Compound C under heating with K2 CO3 in methanol produces estetrol (compound D) (Scheme 1). The overall yield of this three step process was, starting from estrone 3-hydroxyestetra-1,3,5(10),15-tetraen-17-one, only about 7%.

Verhaar M. T; et al (WO 2004/041839) describes a process for the preparation of estetrol by cis hydroxylation of 17-acetyloxy-3-benzyloxy-estra-1,3,5(10),15-tetraene using osmium tetraoxyde and trimethyl-amine N-oxide in THF at 50° C. The resulting 15,16-dihydroxylated crude derivative was obtained in 84% yield but several crystallizations were needed in order to purify this intermediate. Finally the yield after these purifications was about 43%.
Bull, James R; et al in Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (2), 241-51; 1990 described cis hydroxylation using osmium tetraoxyde on a 14,17-ethano derivative of formula (E) wherein Pa is a methyl group and Pb is an acetyl group. A mixture was obtained consisting of about 56% of the α,α-dihydroxy and 27% of the β,β-dihydroxy derivative.

Beside the poor selectivity for osmium-catalyzed dihydroxylation of these 17β-acetyloxy derivatives, exhaustive purifications are needed.
There remain a need for an improved synthesis of estra-1,3,5 (10),15α,16α,17β-tetrol (estetrol).
It is therefore an object of the present invention to provide a process for the preparation of estra-1,3,5(10)-triene 15α,16α,17β-tetrol which overcome at least one the disadvantages of the prior art.